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Neonatal Exposure to Estradiol Valerate Programs Ovarian Sympathetic Innervation and Follicular Development in the Adult Rat¹

Laboratory of Neurobiochemistry, Department of Biochemistry and Molecular Biology, Faculty of Chemistry and Pharmaceutical Sciences, University of Chile, Santiago 838-0492, Chile

ABSTRACT

A single injection of estradiol valerate (EV) to 14-day-old rats (when the ovarian follicle population has been already established) disrupts cyclicity, increases the activity of key enzymes of androgen biosynthesis, and develops polycystic ovary by a causally related increase in ovarian noradrenaline (NA). The current study examined an early window of ovarian development to look for a specific stage of development at which estradiol can induce such changes in sympathetic activity and follicular development. A single dose of EV applied to rats before the first 12 h of life rapidly increases (after 24 h) the ovarian expression of nerve growth factor (Ngfb) and p75 low-affinity neurotrophic receptor (Ngfr) mRNAs. When adults, rats presented early vaginal opening, disrupted cyclicity, appearance of follicular cyst, absence of corpus luteum, and infertility. Total follicles decreased, mainly due to a reduced number of primordial follicles, suggesting that estradiol acts in the first stages of folliculogenesis, when primordial follicles are organizing. These changes paralleled a 6-fold increase in NA concentration. No changes in NA content were found in the celiac ganglia, suggesting a local, non-centrally mediated effect of estradiol. Surgical section of the superior ovarian nerve (the main source of sympathetic nerves to the ovary) to rats neonatally treated with EV decreased intraovarian NA, delayed vaginal opening, and blocked the development of follicular cyst and that of preovulatory follicles. Therefore, we can conclude that early exposure to estradiol permanently modifies ovarian sympathetic activity and causes profound changes in follicular development, leading to the polycystic ovary condition.

early development, estradiol, infertility, neonatal estrogenization, neurotransmitters, ovary, ovulation, PCOS, sympathetic nerves

¹Supported by Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT) grant 105-0765 to H.E.L. and grant PG/63/2005 to R.S.Z. (Departamento de Postgrado y Postítulo, Universidad de Chile). R.S.Z. is the recipient of a Ph.D. in Pharmacology fellowship UCH-208 from the Mejoramiento de la Calidad y Equidad de la Educación Superior (MECESUP) Chilean Program.

Correspondence: ²FAX: 56 2 737 8920; e-mail: hlara{at}ciq.uchile.cl